Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are chronic and life-threatening blistering diseases caused by autoantibodies (autoAbs) to the keratinocyte adhesion proteins desmoglein (Dsg) 3 and Dsg1. Left untreated, patients can die from severe blistering of the skin and/or mucous membranes. Current therapy relies on general immune suppression to reduce Ab production, which is effective but risks fatal infection. For example, after B cell depletion with the anti-CD20 monoclonal Ab rituximab, 95% of pemphigus patients experience short-term healing of blisters and 47% achieve complete remission of disease off therapy. However, ~80% of patients relapse, likely due to incomplete CD20+ B cell depletion, and two of 21 patients in the initial trial had serious infections, resultig in one death. Thus, the ideal therapy would eliminate only the disease-causing autoimmune B cells, sparing the vast majority of B cells that help protect against infection. Recently, chimeri T cell receptor (TCR) technology was successfully developed at our institution for cancer therapy. A chimeric antigen receptor (CAR) consists of an extracellular Ab to a cancer antigen fused to T cell cytoplasmic signaling domains. When expressed on the patient's T cells, the CAR directs those T cells to kill antigen-expressing cancer cells and subsequently proliferate to produce memory CAR T cells, leading to complete and durable remission even in refractory cancer patients. In this proposal, we will adapt this powerful technology to engineer T cells to kil autoimmune B cells in pemphigus in order to produce complete and durable remission of autoimmune disease. B cells destined to secrete anti-Dsg3 or anti-Dsg1 Abs express surface anti-Dsg Ab, specifically marking the autoimmune B cells in pemphigus. Because the B cell surface autoAb is now the target, we reversed the typical CAR design to create a chimeric autoAb receptor (CAAR), with the Dsg antigen as the extracellular domain of the chimeric TCR. This proposal will test the hypothesis that Dsg CAARs will provide a highly effective and safe means for killing B cells expressing cell surface anti- Dsg Ab, resulting in disease remission. Completing the aims of the proposal will provide pre-clinical data to justify therapeutic trials in patients, and our unique expertise in CAR technology and pemphigus will help facilitate translation to clinical therapy. This proposal is both innovative and significant because such an approach has never been tested in autoimmune disease and, if proven effective in pemphigus, could be applied to any autoAb-mediated disease for which the target antigen is known.